BG60407B2 - NEW PHARMACOLOGY ACTIVE COMPOUNDS, METHODS OF THEIR PREPARATION AND COMPOSITIONS CONTAINING THESE COMPOUNDS - Google Patents

Abstract

Catechols of the formula wherein r 1 , r 2 , r 3 and x have the meanings given in the description are useful for the treatment of depression, Parkinson's disease, hypertension and heart failure. The invention also relates to methods of preparation and pharmaceutical compositions containing these compounds. 76 claims

Description

The present invention relates to novel pharmacologically active catechols of formula I

x where each of the radicals R ₍ and R ₂ represents hydrogen, optionally substituted acyl or aroyl or lower alkyl carbamoyl; X is an electronegative substituent, in particular a halogen, nitro, cyano or formyl group; and R ₃ is alkyl substituted with lower alkoxy-lower alkoxy, carboxy-lower alkylthio or pyrrole, aralkylidene carbonyl or a group selected from:

f * ^R 4

I and ¹

- CH - C - R, - CH ₂ - C - R, wherein R ₄ is hydrogen, alkyl, cyano or acyl and R _g is cyano, carboxyalkenyl, nitro, acyl, hydroxyalkyl, carboxyalkyl or optionally substituted carbamoyl or aroyl or heteroaroyl or R ₃ is alkoxycarbonyl, with the restriction that R _{4 is} then not hydrogen and when R ₄ is hydrogen or alkyl and R _s is acyl, hydroxyalkyl or aroyl substituted with a hydroxy group, X is then not halogen and that when R ₄ is hydrogen and R ₃ is hydroxyalkyl X is not a nitro group; or R ₄ and R ₅ together with the carbon atom to which they are attached form a 5 to 7 membered substituted cycloalkanone ring;

- (CO) _n (CH ₂ ) _m -COR wherein η is 0 or 1, me 2 fluoro, R 1 is hydroxy, alkyl, carboxyalkyl, optionally substituted alkenyl, alkoxy or substituted amine; and

wherein each of the substituents R1 and R1 is hydrogen or one of the following optionally substituted groups: alkenyl, alkynyl, cycloalkyl and aralkyl, with the proviso that R _g and R are not both hydrogen; or R _g and R ₉ together with the nitrogen atom to which they are attached form, optionally, a substituted piperidyl group.

The invention also relates to simple salts and acid addition salts of the compounds of formula I.

The term "alkyl", as used herein alone or as part of another group, includes straight or branched chain radicals of up to 18 carbon atoms, preferably 1 to 8 carbon atoms, and most preferably 1 to 4 carbon atoms. The term "lower alkyl" as used herein alone or as part of another group includes radicals having from 1 to 7 straight or branched chain carbon atoms, preferably from 1 to 4 and most preferably 1 to 2 carbon atoms. Specific examples of alkyl and lower alkyl residues, respectively, are methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, octyl, decyl and dodecyl, including their various branched chain isomers.

The term "alkenyl" and "alkynyl" means a hydrocarbon moiety as defined above with respect to the term "alkyl" comprising at least one carbon-carbon double bond and a carbon-carbon triple bond, respectively. The alkenyl and alkynyl moieties may contain up to 12 carbon atoms, preferably 1 to 8 and most preferably 1 to 4 carbon atoms.

The term "acylrcyl, as used herein, alone or as part of another group, refers to an alkylcarbonyl or alkenylcarbonyl group, the alkyl and alkenyl groups being defined above.

The term "aroyl", as used herein alone or as part of another group, refers to an arylcarbonyl group, the aryl group being a monocyclic or bicyclic group having 6 to 10 carbon atoms in the ring. Specific examples of aryl groups are phenyl, naphthyl and the like.

The term "alkoxy" as used herein, alone or as part of another group, includes an alkyl moiety as defined above bonded to an oxygen atom.

The term "cycloalkyl" includes saturated cyclic hydrocarbon groups containing

3 to 8 carbon atoms, preferably 5 to 7 carbon atoms. Specific examples are cyclopentyl, cyclohexyl, cycloheptyl and adamantyl groups.

The term "aralkyl" as used herein refers to alkyl groups as defined above substituted with an aryl group. A specific example is the benzyl group.

The term "halogen" as used herein refers to chlorine, bromine, fluorine or iodine, with chlorine and bromine being preferred.

The term "optionally substituted" as used herein in connection with various residues refers to substituents such as halogen, e.g. fluorine, chlorine, bromine, iodine or trifluoromethyl. a group, alkoxy, aryl, alkyl-aryl, halogen-aryl, cycloalkyl, alkylcycloalkyl, hydroxy, alkylamino, alkanoylamino, arylcarbonylamino, nitro, cyano, thiol or alkylthio substituents. The above groups may include 1 to 3, preferably 1 or 2, and in particular one of the above substituents.

The term "heteroaryl" or "heteroaryl" or "heterocycloalkyl" as used herein refers to a monocyclic or bicyclic group containing 1 to 3, preferably 1 or 2, heteroatoms N and / or O and / or S. Specific examples are the morpholinyl, piperidyl, piperazinyl, pyridyl, pyrrolyl and quinolyl groups.

The invention also relates to pharmaceutically acceptable salts of the present compounds.

The present invention also relates to methods of preparing compounds of formula I. According to the invention, compounds of formula I can be prepared, for example, by condensation of an aldehyde of formula II

x where R _p R 1 and X are defined above with a compound of formula III ^R 4

I

CH ₂ - R ₅ III having an active methyl or methylene group and wherein R ₄ and R ₅ have the meanings defined above, with a base or acid catalyzed reaction to give compounds of formula Ia

x where R ₄ and Rj are as defined above and where the double bond can optionally be reduced to a single bond.

The compounds of formula II are also valuable drugs of the invention, new intermediates for the preparation of other valuable products of the invention.

Compounds of formula II wherein X is a cyano group can be prepared from the corresponding compounds wherein X is halogen, preferably bromine, by reaction of these compounds with cuprocyanide in a polar, aprotic solvent such as pyridine, N-methyl pyrrolidone or Ν, Ν -dialkylformamide at elevated temperature 100 - 200 ° C.

Alternatively, compounds of formula II in which X is a 5-cyano group can be prepared by formulating 2,3-dihydroxybenzonitrile with hexamethylenetetramine.

Compounds of formula I according to the present invention can be prepared by condensation of a ketone of formula IV

x in which R _p Rj and X have the meanings defined above and R ₆ represents hydrogen or alkyl, with an aldehyde of formula V

in which R 1 represents hydrogen, alkyl, alkoxy or dialkylamino group to give a compound of formula lb

in which R _p R 1, X, R _t and R ₇ are as defined above.

Compounds of formula I, wherein R ₃ is a substituted alkyl group, can be prepared by the Friedel-Crafts reaction in the presence of aluminum chloride, as by reacting a compound of formula VI activated group with an amine of formula XI

VI

VII in which R, and Rj have the meanings defined above, with cyclic acid anhydride of formula VII

--CO.

⁽ CC>.

where m has a value of from 2 to 7 and, alternatively, with dicarboxylic acid ester chloride of formula VIII

Hal - (CO) - (CHJ -COR

2, m

VIII c is a halogen atom to yield a compound of formula IX wherein m is in the range of 2 to 7, η is an interval 0 - 1, R is defined above and Na!

<CO), (CHj) _ - cor IX wherein the aromatic ring is the substitution _h ira group X to give a compound of formula 1c

(CO), (CH ₂ ) _F - COR.

1c in which R, R _p R ₂ and X are as defined above.

In the compounds of formula Ic, the carbonyl group can be reduced to the methylene group by conventional methods (Clemensen and Wolf-Kischner reduction) to give compounds of formula Id

The compounds of the present invention, wherein Rj is substituted urea group may be prepared by reacting an activated derivative of a benzoic acid of formula X in which R _g and R, are as defined above, to give a compound of formula 1f

COY in which R _p Rj and X are defined above and Y is halogen or any other in which Rj, Rj, X, R _g and R have the meanings defined above.

The invention also relates to compositions in which the compounds of formula I can be used as an active drug component. The compositions may contain the compounds of formula I alone or in combination with some other drugs. For the treatment of Parkinson's disease, the compounds of formula I are administered with levodopa, either individually or in a common composition. Peripheral dopamine decarboxylase (DDC) inhibitors such as carbidopa or benserazide may also be included in the composition, although they are optional.

The compounds of the present invention may be administered in various dosage forms for administration by any suitable enteral or parenteral route. Dosage forms such as tablets, dragees, injectable liquids, etc. can be prepared in a manner known in the art. Any pharmaceutically acceptable additives, glidants, fillers, etc. may be used. for modifying different properties of dosage forms.

Catechol-O-metaltransferase (COMT) catalyzes the transfer of the metal group from B-adenosyl-L-methionine to a number of compounds with a catechol structure. This enzyme is important for the extracorporeal inactivation of catecholamines and drugs with catechol structure. COMT is one of the most important enzymes involved in catecholamine metabolism. It is present in many tissues, both in the peripheral and central nervous systems. The highest activity is found in the liver, small intestine and kidneys. COMT is probably present in soluble and membrane bound forms. The exact nature of the two forms has not been established.

In Parkinson's disease, dopaminergic neurons, mainly nigrosatrial neurons, are damaged and dopamine deficiency occurs in the cerebral basal ganglia. This deficiency can be compensated by levodopa, which becomes dopamine in the central nervous system under the influence of DDC.

Currently, treatment with levodopa is almost invariably supplemented with a peripheral DDC inhibitor to suppress the early formation of dopamine and thereby increase the cerebral concentration of levodopa and reduce the peripheral side effects of dopamine.

In addition to DDC, COMT metabolizes levodopa, converting it to 3-0-methyldopa (3-OMD). 3-OMD easily penetrates the blood brain barrier through the active transport system. He himself is therapeutically ineffective and harmful in competition with levodopa. 3-OMD accumulates in the tissues due to its long half-life (about 15 hours) compared to levodopa (about 1 hour). The high activity of COMT clearly correlates with the poor efficacy of levodopa despite the presence of a peripheral DDC inhibitor.

In addition to monoamine oxidase (MAO), COMT is the major enzyme involved in the metabolism of amines. By inhibiting the metabolism of endogenous amines (dopamine, noradrenaline, adrenaline) in the brain, COMT inhibitors reduce the breakdown of these compounds. Thus, they can be useful for the treatment of depression.

By effectively inhibiting peripheral COMT, inhibitors direct the levodopa metabolic pathway to decarboxylation, thus producing more dopamine, which is important for the treatment of hypertension and heart failure.

The compounds of the invention are extremely effective COMT inhibitors. They are opening up new, previously unknown options for treating Parkinson's disease. In addition, the new compounds may also be useful in the treatment of depression and heart failure, as well as in hypertension.

New COMT inhibitors that suppress 3-OMD formation may reduce the adverse effects of long-term use of levodopa. In addition, levodopa doses may be reduced. It has been shown that levodopa doses can be reduced by half or one third of the dose used without a COMT inhibitor. Because levodopa dosage is individual, it is difficult to give any absolute dosage, but low daily doses of 25-50 mg are satisfactory for initiation of treatment.

Preliminary clinical trials with nbutylgalate, a known COMT inhibitor, in patients with Parkinson's disease show a pronounced beneficial effect of n-butylgalate. However, the study was discontinued due to the very high toxicity of n-butylgalate.

The COMT inhibitory effect of the compounds of the invention has been tested using the following experimental procedures.

Determination of COMT activity in vitro. The in vitro activity of COMT was determined in enzyme preparations isolated from the brain and liver of Han: WlST female rats, weighing. 100 g. The rats were sacrificed with carbon dioxide, the tissues were removed and stored at -80 ° C until enzyme activity was determined.

The enzyme preparation was prepared by homogenizing the tissues in 10 mM phosphate buffer, pH 7.4, (1:10 w / g) containing 0.5 mM dithiothreitol. The homogenate was centrifuged at 15,000 x G for 20 min. The fluid floating above was centrifuged at 100,000 x G for 60 min. All procedures were performed at + 4 ° C. The liquid floating above from the last centrifugation (100,000 x G) was used to determine the activity of the dissolved COMT enzyme.

Determining 1C _Piss performed by measuring the COMT activity in several drug concentrations of the reaction mixture containing enzyme preparation, 0.4 mM dihydroxybenzoic acid (substrate), 5 mM magnesium chloride, 0.2 mM S-adenosyl-L-methionine and COMT inhibitor in 0.1 M phosphate buffer, pH 7.4. The COMT inhibitor was not added to the control. The mixture was incubated for 30 min at 37 ° C, after which the reaction was stopped with perchloric acid and the precipitated proteins were separated by centrifugation 4000 x G for 10 min. The enzyme activity was measured by determining the concentration of 3 -methoxy-4-hydroxybenzoic acid formed from COMT (dihydroxybenzoic acid) substrate using HPLC using an electrochemical detector. Chromatography was performed by injecting 20μ 1 of the sample into a 4.6 mm x 150 mm Spherisorb ATM ODS column (particle size 5 μ 1). The reaction product was eluted from the column with 20% methanol containing 0.1 M phosphate, 20 mM citric acid and 0.15 mM EDTA, pH 3.2, at a flow rate of 1.5 ml / min. The electrochemical detector was adjusted to 0.9 V against an Ag / AgCl electrode. The concentration of the reaction product, 3-methoxy-4-hydroxybenzoic acid, was compared with controls and samples containing a COMT inhibitor. The _IC10 value is the concentration that causes a 50% decrease in COMT activity.

Effect of COMT inhibitors in vivo. Han - WIST rats weighing 200-250 g were used in the experiment. The control group was given 50 mg / kg of carbidopa 30 min before levodopa (50 mg / kg). The test group was also given carbidopa 50 mg / kg 30 min before levodopa + COMT inhibitor. The drug is administered orally.

Sampling. About 0.5 ml of blood is drawn from the caudal artery. The sample was allowed to coagulate in ice, then centrifuged and serum separated. The serum was stored at -80 ° C until the concentration of levodopa and its metabolite 3-OMD was determined.

Determination of the serum concentration of levodopa and 3-OMD.

An equal volume of 0.4 M perchloric acid, 0.1% sodium sulfate, 0.01% EDTA containing dihydroxybenzylamine as internal standard was added to the serum (eg 100 μl). The sample was stirred and kept in ice until the proteins were removed by centrifugation (4000 x G for 10 min) and the concentration of levodopa and 3-OMD was determined by HPLC using an electrochemical detector. The compounds were separated into a 4.6 mm x 150 mm Ultrasphere ODS column in eluent containing 4% acetonitrile, 0.1 M phosphate buffer, 20 mM citric acid, 0.15 mM EDTA, 2 mM octylsulfonic acid and 0.2% tetrahydrofolane , pH 2.8. The flow rate is 2 ml / min. The electrochemical detector is adjusted to +0.8 V relative to an Ag / AgCI electrode. The concentration of test compounds was determined by comparing the highest of the peaks with that of the internal standard. The ratio was used to calculate the serum concentration of levodopa and 3-OMD in control rats and those given a COMT inhibitor.

Results. The best COMT inhibitors of the invention are more than a thousand times more potent in vitro than the most commonly known compound U-0521 (Table 1). Oral administration of COMT inhibitors also showed a significant inhibition of serum 3OMD production more than U-0521 (Table 2). The compound U-0521 further penetrates the blood-brain barrier and inhibits tyrosine hydroxylase activity, thereby blocking the biosynthesis of vital catecholamines. In contrast, the compounds of the invention are COMT specific and do not significantly penetrate the blood-brain barrier.

Table 1 ^R !

In vitro results ^R 2

COMT inhibition in brain tissue (IC _j0 nM)

20 osn, and y-os, 'osn, 5 N. 5-NO, dream - dream - p 0 N. 25 5-NO, Mon-Fri -Ϊ-Ο Fr. 6

30 CH - c - c - c. N. 5-NO, 1 II CH, 0 12

5-NO ₂

n n 40 5-NO, n N. 45 5-NO, n N. 5-ΝΟζΟ

(CH,) .CON - CH - C = CH 20 1 CH ₃ dream - dream - dream - dream, 1 1 23 ¹ 1 dream _{3 he} (CH ₂ ) ₄ CONH 27

Table 1 (continued)

Example compound

R1 R ₂ X

COMT inhibition in brain tissue ( _IC10 nM) ¹⁰ _{cm 3}

25 N. N. 5-NO ₂ 15 (CHJ.CONH - CH 1 ^CH h 33 23 H - N. 5-NO ₂ CH ₂ CH ₂ CH ₂ CH ₂ COOH 90 42 N. N. 5-CI 20 ^c ° ^nh O> 400 U-0521 N. N. 5-H 25 COCH - dream ₃ 6000

CH ₃

In vivo results 35

Table 2

Oral dose Compound 3-OMD concentration% of control 1 hour 5 hours 30 mg / kg Example 4 4 ° - 96 -98 30 mg / kg Example 5 - 84 - 49 30 mg / kg Example 10 45 - 63 - 26 30 mg / kg Example 7 - 58 - 34 100 mg / kg Example 23 - 86 - 41 100 mg / kg U - 0521 ⁵⁰ - 34 - 14

The results show that the compounds of the invention are even more than a thousand times more potent in vitro (Table 1) than the comparator (U-0521). The orally administered novel compounds also 5 inhibited COMT significantly better than the comparator, which was reflected as a decrease in serum 3-OMD concentration (Table 2). Comparative compound U-0521 also penetrates the blood-brain barrier and non-specifically inhibits tyrosine hydrolase, which is important for catecholamine biosynthesis.

DESCRIPTION OF THE FIGURES Attached.

Figure 1 shows the serum 3-OMD concentration for the novel compound (e.g., cf10 according to Example 4) and for the control compound that does not contain a COMT inhibitor. The design of the experiment is the same as for the in vivo experiment above.

Figure 2 shows serum levodopa concentrations after the same treatment.

These figures show that the compounds of the invention increase the bioavailability of levodopa and reduce the level of the harmful metabolite 3-OMD. The observed change in serum is reflected in the brain concentrations of 3-OMD and levodopa.

Specificity of COMT inhibition.

The new compounds are specific COMT inhibitors and not inhibitors of other important enzymes. This is illustrated in the in vitro experiments that were carried out as described above.

1C ₅₀ (nM)

Compound example COMT TH DBH DDC MAO-D MAO-V 10 5 18,000 > 50,000 > 50,000 > 50,000 > 50,000 7 6 21,000 > 50,000 > 50,000 > 50,000 > 50,000 5 12 50,000 > 50,000 > 50,000 > 50,000 > 50,000 4 20 21,000 > 50,000 > 50,000 > 50,000 > 50,000 U-0521 6000 24,000 > 50,000 > 50,000 > 50,000 > 50,000

TH = tyrosine hydroxylase, DBH = dopamine-β-hydroxylase MAO-A and MAO-B = monoamine oxidase-A and monoamine oxidase-B.

The COMT inhibitors of the invention are extremely specific. They inhibit COMT effectively at low concentrations, whereas inhibition of other enzymes involved in catecholamine metabolism requires a concentration of 1000 to 10000 times higher. The difference between the inhibition of TH and COMT in the comparative compound U-0521 is only 4-fold.

IC _J0 is the concentration which inhibits 50% of the enzyme activity.

Toxicity.

The new COMT inhibitors are non-toxic. For example, LD _J0 of 3- (3,4-dihydroxy-

5-Nitrophenyl) -1- (3,4,5-trimethoxyphenyl) prop-2-en-1-one (Example 10) given as an oral suspension to rats is above 2500 mg / kg.

EXAMPLES FOR IMPLEMENTATION

OF THE INVENTION

Example 1. 3-Nitro-5- [2- (4-pyridyl) vinyl] catechol. A solution containing 2.0 g (0.011 mol) of 3,4-dihydroxy-5-nitrobenzaldehyde and 2.23 g (0.024 mol) of 4-picoline in 9.0 ml of acetic anhydride was refluxed for 1 hour. About 15 ml of isopropanol is then added and the solution is cooled to 0 ° C by crystallizing the diacetyl derivative of the desired product. After filtration, the product was suspended in 100 ml of 0.5 N hydrochloric acid and refluxed for 1.5 hours. After cooling, the precipitate was filtered off, washed with water and acetone and dried. Yield 1.89 g (67%), m.p. above 350 ° C.

Example 2. 3-Nitro-5- [2- (4-quinolyl) vinyl] catechol. Repeat the procedure described in Example 1 using 2.0 g (0.011 mol) of 3,4-dihydroxy-5-nitrobenzaldehyde and

3.44 (0.024 mol) 4-quinaldine. Yield 1.7 g (50%), m.p. 250 ° C (dec.).

Example 3. 3,4-Dihydroxy-5, xn dinitrostyrene. A solution containing 3.66 g (0.02 mol) of 3,4-dihydroxy-5-nitrobenzaldehyde, 3.66 g (0.06 mol) of nitromethane and 3.31 g of ammonium acetate in 10 ml of absolute ethanol was heated under reflux for 6 hours. Water was added to the reaction mixture. The mixture was acidified with hydrochloric acid and extracted with methylene chloride. The methylene chloride extract was washed with water and the solvent was evaporated in vacuo. The residue was crystallized from isopropanol. Yield 1.9 g (40%), m.p. 258260 ° C.

EXAMPLE 4 3,4-Dihydroxy-5-nitro-, n-dicyanostyrene. Repeat the procedure described in Example 3 using 3.0 g

3,4-dihydroxy-5-nitrobenzaldehyde and 3.0 g malonodinitrile. The product crystallizes from methanol-water. Yield 1.9 g (50%), m.p. 205-209 ° C.

Example 5. 4- (3,4-Dihydroxy-5-nitrophenyl) -3-methylbut-3-en-2-one. A solution containing 0.5 g of 3,4-dihydroxy-5-nitrobenzaldehyde in 2.0 ml of butanone was saturated with hydrogen chloride gas. After standing overnight, ether was added to the solution and filtered. The product crystallizes from isopropanol. Yield 0.2 g (30%), m.p. 139-141'C.

Example 6 3- (3,4-Dihydroxy-5-nitrobenzylidene) -2,4-pentanedione. A solution containing 1.83 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 1.00 g of 2,4-pentanedione in 10 ml of tetrahydrofuran was saturated with hydrogen chloride gas. After standing overnight at 5 ° C, the product was filtered and washed with ether. Yield 1.2 g (50%), m.p. 175-178 ° C.

Example 7 3- (3,4-Dihydroxy-5-nitrophenyl) -1-phenylprop-2-en-1-one. A solution containing 0.55 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 0.36 g of acetophenone in 10 ml of methanol was saturated with hydrogen chloride gas. After standing at 5 ° C overnight, the product was filtered and washed with methanol. Yield 0.55 g (68%), m.p. Mp 192-195 ° C.

Example 8. 3- (3,4-Dihydroxy-5-nitrophenyl) -1- (4-methoxyphenyl) -prop-2-en-1-one. The procedure of Example 7 was repeated using 1.8 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 1.5 g of 4'-methoxyacetophenone in 20 ml of tetrahydrofuran. Yield 1.88 (60%); 222228 ° C.

Example 9. 3- (3,4-Dihydroxy-5-nitrophenyl) -1- (3,4-dimethoxyphenyl) -prop-2-en-1 one. Repeat the procedure described in Example 7 using 1.8 g of 3,4-dihydroxy-

5-nitrobenzaldehyde and 1.8 g of 3 ', 4'-dimethoxyacetophenone in 20 ml of methanol. Yield 1.7 g (50%), m.p. 206-208 ° C.

Example 10. 3- (3,4-Dihydroxy-5-nitrophenyl) -1- (3,4,5-trimethoxyphenyl) -prop-2en-1-one. Repeat the procedure described in Example 7 using 0.55 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 0.63 g of 3 ', 4', 5'trimethoxyacetophenone. Yield 0.50 g (44%), m.p. 213-216 ° C.

Example 11. 3- (3,4-Dihydroxy-5-nitrophenyl) -1- (2-hydroxyphenyl) -prop-2-en-1-one. Repeat the procedure described in Example 7 using 1.0 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 0.74 g of 2'-hydroxyacetophenone. Yield 0.2 g (12%), m.p. Mp 231-234 ° C.

Example 12 3- (3,4-Diacetoxy-5-nitrophenyl) -1-phenylprop-2-en-1-one. A solution containing 1.0 g of the product obtained in Example 7 in 5.0 ml of acetic anhydride was refluxed for 2 hours. After cooling, the product was filtered and washed with ether. Yield 0.73 g (68%), m.p. 183-185 ° C.

Example 13 3- (3,4-Dibenzyloxy-5-nitrophenyl) -1-phenylprop-2-en-1-one. 1.0 g of the product obtained in Example 7 and 2.0 ml of benzoyl chloride were dissolved in 5 ml of tetrahydrofuran. Most of the tetrahydrofuran is distilled off and the residue is refluxed for 2 hours. After cooling, ether was added to the mixture and the product was filtered and treated for crystallization with ethylmethylketone. Yield 0.50 g, m.p. Mp 206-210 ° C.

Example 14 3- (3-pivaloyloxy-4-hydroxy-5-nitrophenyl) -1-phenyl prop-2-en-1-one. 1.0 g of the product obtained in Example 7 was dissolved in 5 ml of tetrahydrofuran, added

4.7 ml of pivaloyl chloride and the mixture was refluxed for 16 hours. The solvent was evaporated in vacuo and the residue purified on a silica gel column using a mixture of toluene-acetic acid dioxane (18: 1: 1) as eluent. The product crystallizes from ether, m.p. 148-150'C.

Example 15. 4- (3,4-Dihydroxy-5-nitrophenyl) -3-methylbut-3-en-2-ol. 1.8 g of the product obtained in Example 5 was dissolved in 20 ml of 1N NaOH solution and 4.0 g of sodium borohydride was added in a small amount of water. The mixture was stirred overnight at room temperature, acidified with hydrochloric acid and extracted with ether. The solvent was evaporated in vacuo and the residue purified on a silica gel column using toluene-acetic acid-dioxane (18: 1: 1). The product was crystallized from dichloromethane-petroleum ether. Yield 0.80 g (44%), m.p. 102104 ° C.

Example 16. 7- (3,4-Dihydroxy-5-nitrobenzylidene) -8-ketononic acid. Repeat the procedure described in Example 8 using 1.83 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 1.72 g of 8-ketonanic acid. Yield 1.85 g (55%), yellow viscous oil.

Example 17. 4'-hydroxy-3'-methoxy-5'nitroacetophenone. To a solution containing 40 ml of nitric acid (d = 1, 41) and 40 ml of water was gradually added under cooling (below 7 ° C) and stirring 25,0 g of 4'-hydroxy-3'-methoxyacetophenone. After stirring for 0.5 h at 0 ° C, the product was filtered off, washed first with dilute nitric acid (1: 1) and then with water. Yield 24.0 g (75%). The Я-NMR spectrum corresponds to the defined structure.

Example 18 3 ', 4'-Dihydroxy-5'-nitroacetophenone. A solution containing 19.9 g of the product obtained in Example 17 in 200 ml of acetic acid and 200 ml of 48% hydrobromic acid was refluxed for 5 hours. To the reaction mixture was added 500 ml of saturated sodium sulfate solution and allowed to stand at 5 ° C overnight. The solution was extracted with ether. The ether phase was washed with 200 ml of water, dried and the solvent was evaporated in vacuo. The residue was crystallized from isopropanol. Yield

10.2 g (55%); Mp 155-159 ° C.

Example 19.1- (3,4-Dihydroxy-5-nitrophenyl) -3- (4-dimethylaminophenyl) -prop-2-en1-one. A solution containing 0.5 g of the product obtained in Example 18 and 0.38 g of 4-dimethylaminobenzaldehyde in 5 ml of methanol was saturated with hydrogen chloride gas. The solution was refluxed for 1 hour. After cooling, the product was filtered and washed with methanol. Yield 0.26 g (70%), decomposition upon heating.

Example 20. 5- (4-Benzyloxy-3-methoxyphenyl) -2,4-pentadienoic acid. To a solution containing 260 g of 4-benzyloxy-3-methoxybenzaldehyde and 200 ml of crotonic acid ethyl ester in 1200 ml of N-methylpyrrolidone was added gradually with stirring and cooling at 0 ° C 149.6 g of potassium tert-butoxide. The solution was stirred for 0.5 h, then 200 ml of IOH NaOH solution was added and stirred for a further 0.5 h at 0 ° C. The reaction mixture was added to a mixture of hydrochloric acid and ice. The semi-solid product was separated and used in the next step without further purification.

Example 21 5- (4-Hydroxy-3-methoxyphenyl) pentanoic acid. The crude product obtained in Example 20 was dissolved in 500 ml of dimethylformamide and a catalyst of 10% palladium on carbon 22 g was added. The mixture was hydrogenated at 60 ° C and normal pressure until the theoretically calculated amount of hydrogen (3 moles) was consumed. After filtration, the large amount of solvent was evaporated in vacuo and the residue was dissolved in 1 L of dichloromethane and washed with 2 L of water. The product was extracted with 1.5 l of saturated NaHCO ₃ solution. After acidification of the aqueous phase with hydrochloric acid, the product is extracted with 1 L of dichloromethane. The solvent was distilled off in vacuo and the semi-solid residue (180 g) was used in the next step.

Example 22 5- (4-Hydroxy-3-methoxy-5-nitrophenyl) pentanoic acid. The above product (180 g) was dissolved in 1 L of dichloromethane and 820 ml of 1 molar solution of HNO ₃ dichloromethane were gradually added with stirring and cooling (0-5 ° C). The solution was stirred for a further 10 min at 0 ° C, then water was added. The organic phase was separated and washed with water. The solvent was evaporated in vacuo and the semi-solid residue was used as such in the next step.

Example 23. 5- (3,4-Dihydroxy-5-nitrophenyl) pentanoic acid. The above product, obtained in Example 22, was dissolved in a mixture containing 500 ml of acetic acid and 500 ml of 48% hydrobromic acid and refluxed for 4 hours. A saturated solution of Na ₂ SO ₄ was added to the reaction mixture and the solution was allowed to stand at 5 ° C overnight. The crystallized product was filtered and washed with 50% acetic acid. This product was recrystallized from ethyl acetate. Yield 32 g (16%), m.p. 135-138 ° C.

Example 24 1-Benzyl-4- [5- (3,4-dihydroxy-5-nitrophenyl) pentanoyl] -piperazine hydrochloride. A solution containing 3.0 g of the product obtained in Example 23 in 18 ml of thionyl chloride was refluxed for 10 minutes. The excess thionyl chloride was evaporated in vacuo and the formed acid chloride was dissolved in 20 ml of dichloromethane. To this solution was added 2.1 g of 1-benzylpiperazine in 20 ml of dichloromethane with stirring, followed by stirring for another 0.5 hour. Ether was added to the reaction mixture and the crystals were filtered. Yield 3.55 g (73%), m.p. 8589 ° C.

Example 25. N -isopropyl-5 (3,4-dihydroxy-5-nitrophenyl) -pentanoic acid amide. A solution containing 0.5 g of the product obtained in Example 23 in 2.5 ml of thionyl chloride was refluxed for 10 minutes. The excess thionyl chloride was evaporated in vacuo and the residue was dissolved in 25 ml of dichloromethane. To this solution was added 0.47 g of isopropylamine and the mixture was stirred for 1 hour at 20 ° C. The dichloromethane phase was washed with 1N hydrochloric acid and evaporated in vacuo. The residue was crystallized from toluene. Yield 0.44 g (75%), m.p. 113-115 ° C.

Example 26 Ν-Μετ »υι- (Ν-προpargyl-5- (3,4-dihydroxy-5-nitrophenyl) pentanoic acid amide. Repeat the procedure described in Example 25 using 0.5 g methylpropargylamine instead Yield 0.5 g (83%), mp 133-135'C.

Example 27. The amide of b1- (1-adamantyl) -

5- (3,4-Dihydroxy-5-nitrophenyl) pentanoic acid. Repeat the procedure described in Example 25 using 1.5 g of 1-aminoadamantane instead of isopropylamine. Yield 0.61 g (80%), m.p. Mp 157-160 ° C.

Example 28. Tetradecyl ester of

5- (3,4-Dihydroxy-5-nitrophenyl) pentanoic acid. Repeat the procedure described in Example 25 using 1.26 g of 1-tetradecanol instead of isopropylamine. The reaction mixture was washed with water and the solvent was evaporated in vacuo. Yield 0.44 g (50%), m.p. 46-47 ° C.

Example 29 5 (3,4-Diacetoxy-5-nitrophenyl) pentanoic acid tetradecyl ester. A solution containing 0.1 g of the product obtained in Example 28 in 2 ml of acetic anhydride was refluxed for 20 minutes. The solvent was evaporated in vacuo and the residue was crystallized from petroleum ether (b. 40 ° C) m.p. 52-54 ° C.

Example 30. Tetradecyl ester of

5- (4-Hydroxy-3-pivaloyloxy-5-nitrophenyl) pentanoic acid. Repeat the procedure described in Example 29 using ml pivaloyl chloride instead of acetic anhydride. The product is viscous oil.

Example 31 5- (3,4-Dimethoxy-5-chlorophenyl) -2,4-pentadienoic acid. To a solution containing 10.0 g of 3,4-dimethoxy-5-chlorobenzaldehyde and 8.3 ml of ethyl crotonate in 65 ml of N-methylpyrrolidone was added 6.7 g of potassium tert-butoxide with stirring. The solution was stirred for an additional 0.5 h at 20 ° C and then poured into a mixture of ice and hydrochloric acid and extracted with ether. The ether extract was washed with water and then extracted with NaHCO ₃ solution. The aqueous phase was acidified with hydrochloric acid and the semi-solid product was separated and washed with water. Yield: 7.3 g (55%).

Example 32 5- (3,4-Dimethoxy-5-chlorophenyl) pentanoic acid. Solution containing

6.2 g of the above product obtained in Example 31 were dissolved in a mixture of 30 ml of acetic acid and ml of concentrated hydrochloric acid. Palladium on carbon (10% Pd) catalyst was added and the mixture was hydrogenated at normal pressure and room temperature. After filtration, the solvent was evaporated in vacuo. Yield:

3.2 g (55%), viscous oil.

Example 33 5- (3,4-Dihydroxy-5-chlorophenyl) pentanoic acid. Solution containing

3.2 g of the above product in 8 ml of acetic acid and 10 ml of 48% hydrobromic acid was refluxed for 3 hours. A saturated solution of Na ₂ SO ₄ in water was added to the reaction mixture. The crystallized product was filtered off, washed with water and recrystallized from toluene, m.p. 99-101 ° C.

Example 34 3- (3,4-Dihydroxy-5-nitrophenyl) -1- (4-methylphenyl) -prop-2-en-1-one. To a solution containing 5.49 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 5.37 g of 4'-methylacetophenone in 50 ml of tetrahydrofuran was added a catalytic amount of hydrogen chloride gas and refluxed for 4.5 hours. The solvent was evaporated in vacuo and the residue was crystallized from ether-petroleum ether. Yield: 1.85 g, m.p. 184186 ° C.

Example 35 N- (1-adamantyl) -3,4-diacetoxy-5-nitrobenzamide. A solution containing 0.85 g of 3,4-diacetoxy-5-nitrobenzoic acid and 0.32 ml of thionyl chloride and a catalytic amount of N, N-dimethylformamide in 10 ml of toluene was heated at 80 ° C for 1 hour. The solvent was evaporated in vacuo and the residue dissolved in 5 ml of dichloromethane and added to a mixture containing 0.56 g of 1-aminoadamantane hydrochloride and 0.94 ml of triethylamine in 10 ml of dichloromethane and stirred for 15 min at 0 ° C. and then for 15 min at 20 ° C. Water was added to the reaction mixture and the dichloromethane phase was separated. The solvent was evaporated in vacuo to give a yellow viscous oil of 1.2 g (100%).

Example 36. N- (1-adamantyl) -3,4-dihydroxy-5-nitrobenzamide. A solution containing 1.2 g of the product obtained in Example 35 and a catalytic amount of sulfuric acid in 10 ml of methanol was refluxed for 3 hours. 20 ml of water were added and upon cooling crystallized 0.85 g (89.5%) of the desired product, m.p. 207-208 ° C.

Example 37 4-Cyclohexylcarbonyl 1- (3,4-diacetoxy-5-nitrobenzoyl) piperidine. Repeat the procedure described in Example 35 using 0.58 g of cyclohexylcarbonylpiperidine and 0.38 g of 2,6-lutidine instead of 1-aminoadamantane hydrochloride and triethylamine, respectively. Yield: 1.2 g (87%), a viscous yellow oil.

Example 38. 4-Cyclohexylcarbonyl 1- (3,4-dihydroxy-5-nitrobenzoyl) piperidine. The procedure of Example 36 was repeated using 1.2 g of the product obtained in Example 45. Yield: 0.5 g (50%), m.p. Mp 155-165 ° C.

Example 39. L1-Benzyl-3,4-diacetoxy-5nitrobenzamide. 0.75 g of 3,4-diacetoxy-5-nitrobenzoic acid was converted to the corresponding acid chloride as described in Example 35. It was dissolved in 5 ml of dichloromethane and added to a solution containing 0.27 ml of benzylamine and 0. 5 ml of 2,6-lutidine in 7 ml of dichloromethane. Yield: 0.95 g (96%), viscous oil.

Example 40. N-Benzyl-3,4-dihydroxy-5-nitrobenzamide. Repeat the procedure described in Example 36 using 0.95 g of the product obtained in Example 47. Yield: 0.5 g (68%), m.p. Mp 185-189 ° C.

Example 41 b1- (1-adamantyl) -3,4-diacetoxy-5-chlorobenzamide 0.7 g of 3,4-diacetoxy-

5-Chlorobenzoic acid was converted to the corresponding acid chloride and the procedure described in Example 35 was repeated. Yield: 1.0 g (95

%), viscose oil.

Example 42.1 N- (1-adamantyl) -3,4-dihydroxy-5-chlorobenzamide. The product of Example 41 was deacetylated as described in Example 36. Yield: 0.6 g (78%), m.p. Mp 244-247 ° C.

Example 43. N- (1-adamantyl) -3,4-diacetoxy-5-cyanobenzamide. 0.6 g of 3,4-diacetoxy-

5-Cyanobenzoic acid was converted to the corresponding acid chloride and the procedure described in Example 35 was repeated. Yield: 0.75 g (88%), a viscous oil.

Example 44. L1- (1-adamantyl) -3,4-dihydroxy-5-cyanobenzamide. 0.75 g of the above product was deacetylated as described in Example 36. Yield: 0.5 g (89%), m.p. 253-255 ° C.

Example 45 3- (3-Ethoxycarbonylmethylcarbamoyloxy-4-hydroxy-5-nitrophenyl) -1-phenylprop-2-en-1-one. 1.5 g of ethylisocyanatoacetate was added to a solution containing 0.54 g of the product obtained in Example 7 in 10 ml of THF and the solution was stirred for 3 days at 20 ° C. The solvent was evaporated under reduced pressure and the crude product was purified on a silica gel column using toluene dioxane-acetic acid (8: 1: 1) as eluent. Crystallization from acetone-petroleum ether gave 0.13 g (17%) of the desired product, m.p. Mp 155-158 ° C.

Example 46 3- (3,4-Dihydroxy-5-nitrophenyl) -1- (2-carboxyphenyl) -prop-2-en-1-one. Repeat the procedure described in Example 7 using 1.83 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 1.64 g of 2'-nitroacetophenone. Yield: 0.36 g (11%); 178-180 ° C.

Example 47 3- (3,4-Dihydroxy-5-nitrophenyl) -1- (4-nitrophenyl) -prop-2-en-1-one. Repeat the procedure described in Example 7 using 1.83 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 1.65 g of 4'-nitroacetophenone. Yield: 1.25 g, (38%); Mp 255-256 ° C.

Example 48 2,5-bis- (3,4-dihydroxy-5-nitrobenzylidene) cyclopentanone. Repeat the procedure described in Example 7 using 5.0 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 2.0 g of cyclopentanone. Yield: 4.4 g (78%); 300 ° C (dec.).

Example 49 1-Phenyl-3- (3-stearoyloxy-4-hydroxy-5-nitrophenyl) -prop-2-en-1-one. A solution containing 2.0 g of the product obtained in Example 7 and 10.0 g of stearoyl chloride in 10 ml of dioxane was stirred and heated for 18 hours at 90 ° C. After cooling, petroleum ether was added and the product filtered. Recrystallization from dichloromethane-petroleum ether gave 0.64 g (17%) of the desired product, m.p. 112-118 ° C.

Example 50 2-Cyano-3 (3,4-dihydroxy-5-nitrophenyl) acrylic acid ethyl ester. Repeat the procedure described in Example 3 using 1.0 g of 3,4-dihydroxy-5-nitrobenzaldehyde, 0.9 g of ethyl cyanoacetate and 0.15 g of ammonium acetate in 10 ml of ethanol. Yield: 0.87 g (57%); 205-210 ° C.

Example 51 3- (3,4-Dihydroxy-5-nitrobenzylidene) -4-ketopentanoic acid methyl ester. A solution containing 1.83 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 1.1 glevylanic acid in 10 ml of methanol was saturated with hydrogen chloride gas. The mixture was refluxed for 20 hours, then water was added and the solution was extracted with ether. The solvent was evaporated under reduced pressure and the residue was crystallized from ether-petroleum ether. Yield: 0.54 g (20%), m.p. 142-150 ° C.

Example 52. 3,4-Dihydroxy-5-nitrobenzylmalonitrile. 1.5 g of sodium borohydride was added to a suspension containing 3.7 g of the product obtained in Example 4 in 10 ml of water at room temperature. The solution was stirred for 2 hours, acidified with hydrochloric acid and extracted with ether. The solvent was evaporated in vacuo and the residue was crystallized from methanol-isopropanol. Yield: 1.1 g (30%); 211-215'C.

Example 53 3,4-Dihydroxy-5-nitrobenzylcyanoacetic acid ethyl ester. Repeat the procedure described in Example 52 using 2.78 g of the product described in Example 81. Yield: 0.98 g (35%), yellow viscous oil (68%), m.p. Mp 188-192 ° C.

Example 54. 2-Cyano-3- (3,4-dihydroxy-

5-nitrophenyl) acrylamide. Solution containing

1.3 g of 3,4-dihydroxy-5-nitrobenzaldehyde, 0.73 g of cyanoacetamide and a catalytic amount of piperidine acetate in 40 ml of dry ethanol were refluxed overnight. The solvent was evaporated in vacuo and the residue was recrystallized from water-dimethylformamide. Yield: 0.84 g (48%); 296-298 ° C.

Example 55 N, N-dimethyl-2-cyano-3 (3,4-dihydroxy-5-nitrophenyl) -acrylamide. A solution containing 1.83 g of 3,4-dihydroxy-5-nitrobenzaldehyde, 1.2 g of N, N-dimethylcyano14 acetamide and a catalytic amount of piperidine acetate in 40 ml of dry ethanol was heated at reflux overnight. Yield: 1.1 g (40%); 183-185 ° C.

Example 56. N, N-Diethyl-2-cyano-3- (3,4-dihydroxy-5-nitrophenyl) -acrylamide. The procedure described in Example 55 was repeated using 1.83 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 1.5 g of N, N-diethylcyanoacetamide. Yield: 2.33 g (73%); Mp 153-156 ° C.

Example 57. N-Isopropyl-2-cyano-3 (3,4-dihydroxy-5-nitrophenyl) acrylamide. The procedure described in Example 55 was repeated using 1.83 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 1.3 g of N-isopropylcyanoacetamide. Yield: 1.46 g (50%), m.p. Mp 243-245 ° C.

Example 58. N-Methyl-N-N - [2-cyano-3 (3,4-dihydroxy-5-nitrophenyl) -acryl] piperazine. Repeat the procedure described in Example 55 using 1.83 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 1.7 g of N'-methylN '' - cyanoacetylpiperazine. Yield: 2.16 g (65%); 265 ° C (dec.).

Example 59. 3,4-Dihydroxy-5-nitrobenzyl-2-methoxyethyl ether. A solution of 1.0 g of 3,4-dihydroxy-5-nitrobenzyl alcohol in 5.0 ml of 2-methoxyethanol was refluxed for 1 hour. The solvent was evaporated in vacuo and the residue treated with isopropanol for crystallization. Yield: 0.4 g (30%); Mp 154-157 ° C.

Example 60.3,4-Dihydroxy-5-nitrobenzylthioacetic acid. A solution containing 1.0 g of 3,4-dihydroxy-5-nitrobenzyl alcohol in 5.0 g of thioglycolic acid was stirred for 1.5 hours at 120 ° C. 25 ml of water was added and the product was filtered and washed with water. Yield: 0.25 g (19%), m.p. 91-93'С.

Example 61. 2- (3,4-dihydroxy-5-nitrobenzyl) pyrrole. A solution containing 1.0 g of 3,4-dihydroxy-5-nitrobenzyl alcohol in 5.0 ml of pyrrole in 3.0 ml of dioxane was heated at 100 ° C for 5 hours. Water was added and the solution was extracted with dichloromethane. The solvent was evaporated and the residue purified on a silica gel column using a mixture of toluene-acetic acid-dioxane (18: 1: 1) as eluent. Yield: 0.42 g (33%), m.p. 115-118 ^o C.

Example 62. 2-Cyano-3- (3,4-dihydroxy-

5-nitrophenyl) propanol. To a solution containing 0.85 g of 2-cyano-3- (3,4 dihydroxy-5-nitrophenyl) acrylic acid ethyl ester (Example 50) in 70 ml of dry ethanol was added gradually 0.3 g of sodium borohydride. The solution was stirred for 0.5 h at room temperature, acidified with hydrochloric acid and extracted with ethyl acetate. The solvent was evaporated to give 0.55 g (75%) of yellow crystals, m.p. 149-152 ° C.

Example 63 2-Cyano-3- (3,4-dihydroxy-5-nitrophenyl) acrylic acid neopentyl ester. Repeat the procedure described in Example 3 using 3,4-dihydroxy-5-nitrobenzaldehyde and neopentyl cyanoacetate. Yield: 67%; 173179 ° C.

Example 64 N- (3-hydroxypropyl) -2-cyano-3- (3,4-dihydroxy-5-nitrophenyl) acrylamide. The procedure described in Example 55 was repeated using N- (3-hydroxypropyl) cyanoacetamide and 3,4-dihydroxy-5-nitrobenzaldehyde. Yield: 52%; Mp 223-228 ° C.

Example 65. 3- (4-Hydroxy-5-nitro-3-pivaloyloxybenzylidene) -2,4-pentanedione. A mixture containing 2.0 g of the product obtained according to Example 6 in 5 ml of pivaloyl chloride was heated at 100 ° C for 4 hours. The excess pivaloyloxy chloride was evaporated under reduced pressure and ether was added to the residue. The product was filtered and washed with ether. Yield: 1.41 g (58%); 143-145 ° C.

Claims (76)

Patent claims 1. Compound of formula I: X in which each of the radicals Rj and Rj represents hydrogen, optionally substituted acyl or aroyl or lower alkyl carbamoyl; X is an electronegative substituent, in particular halogen, nitro, cyano or formyl group; and R ₃ is alkyl substituted by a lower alkoxy-lower alkoxy, carboxy lower alkylthio or pyrrole group, aralkylidene carbonyl or a group selected from K. 1 »4 | i - CH - C - 1 - ^ch ₂ “ ch- Rj where R ₄ is hydrogen, alkyl, cyano or acyl and R _s is cyano, carboxyalkenyl, nitro, acyl, hydroxyalkyl, carboxyalkyl or, optionally, substituted carbamoyl or aroyl or heteroaroyl or R ₅ is alkoxycarbonyl, with the proviso that R ₄ is then not hydrogen and that when R ₄ is hydrogen or alkyl and R _s is acyl, hydroxyalkyl or aroyl substituted with hydroxy, X is then not halogen and that when R ₄ is hydrogen and R ₃ is hydroxyalkyl X is not nitro; or R ₄ and R ₅ together with the carbon atom to which they are attached form a 5 to 7 membered substituted cycloalkanone ring; - (CO) _n (CH ₂ ) _m - COR where η is 0 or 1,me2flo7HRe hydroxy, alkyl, carboxyalkyl, optionally substituted alkenyl, alkoxy or substituted amine; and wherein each of the substituents R _g and R ₉ is hydrogen or one of the following, optionally substituted groups: alkenyl, alkynyl, cycloalkyl and aralkyl, with the proviso that R _g and R 1 are not both hydrogen; or R 1 and R 2 , together with the nitrogen atom to which they are attached, form, optionally, an optionally substituted piperidyl group. 2. A compound according to claim 1, wherein X is halogen, nitro, cyano or formyl. 3. 3-nitro-5-[2-(4-pyridyl)vinyl]catechol. 4. 3-nitro-5-[2-(4-quinolyl)vinyl]catechol. 5. 3,4-dihydroxy-5, w -dinitrostyrene. 6. 3,4-dihydroxy-5-nitro- pt, s‘dicyanostyrene. 7. 4-(3,4-dihydroxy-5-nitrophenyl)-3methylbut-2-3-en-2-one. 8. 3-(3,4-dihydroxy-5-nitrobenzylidene)-2,4-pentanedione. 9. 3-(3,4-dihydroxy-5-nitrophenyl)-1-phenylprop-2-en-1-one. 10. 3-(3,4-dihydroxy-5-nitrophenyl)-1(4-methoxyphenyl)-prop-2-en-1-one. 11.3-(3,4-dihydroxy-5-nitrophenyl)-1(3,4-dimethoxyphenyl)-prop-2-en-1-one. 12.3-(3,4-dihydroxy-5-nitrophenyl)-1-(3,4,5-trimethoxyphenyl)-prop-2-en-1-one. 13. 3-(3,4-dihydroxy-5-nitrophenyl)-1-(2-hydroxyphenyl)-prop-2-en-1-one. 14. 3-(3,4-diacetoxy-5-nitrophenyl)-1 phenylprop-2-en-1-one. 15. 3-(3,4-Dibenzoyloxy-5-nitrophenyl)-1-phenylprop-2-en-1-one. 16. 3-(3-pivaloyloxy-4-hydroxy-5-nitrophenyl)-1-phenyl prop-2-en-1-one. 17. 4-(3,4-dihydroxy-5-nitrophenyl)-3-methylbut-3-en-2-ol. 18.7-(3,4-dihydroxy-5-nitrobenzylidene)-8-ketonanoic acid. 19. 1-(3,4-dihydroxy-5-nitrophenyl)-3(4-dimethylaminophenyl)-prop-2-en-1-one. 20. 5-((3,4-dihydroxy-5-nitrophenyl)pentanoic acid. 21. 1-Benzyl-4-[5-(3,4-dihydroxy-5nitrophenyl)-pentanoyl]piperazine hydrochloride. 22. N-Isopropyl-5-(3,4-dihydroxy-5-nitrophenyl)-pentanoic acid amide. 23. N-Methyl-N-propargyl-5(3,4-dihydroxy-5-nitrophenyl)-pentanoic acid amide. 24. N-(1-adamantyl)-5-(3,4-dihydroxy-5-nitrophenyl)-pentanoic acid amide. 25. 5-(3,4-Dihydroxy-5-nitrophenyl)-pentanoic acid tetradecyl ester. 26. 5-(3,4-Diacetoxy-5-nitrophenyl)-pentanoic acid tetradecyl ester. 27. 5-(4-Hydroxy-3-pivaloyloxy-5-nitrophenyl)-pentanoic acid tetradecyl ester. 28. 3-(3,4-dihydroxy-5-nitrophenyl)-1(4-methylphenyl)-prop-2-en-1-one. 29. N-(1-adamantyl)-3,4-diacetoxy-5-nitrobenzamide. 30. N-(1-adamantyl)-3,4-dihydroxy-5-nitrobenzamide. 31. 4-Cyclohexylcarbonyl-1-(3,4-diacetoxy-5-nitrobenzoyl)piperidine. 32. 4-cyclohexylcarbonyl-1-(3,4-dihydroxy-5-nitrobenzoyl)piperidine. 33. M-benzyl-3,4-diacetoxy-5-nitrobenzamide. 34. N-benzyl-3,4-dihydroxy-5-nitrobenzamide. 35. N-(1-adamantyl)-3,4-diacetoxy-5-chlorobenzamide. 36. N-(1-adamantyl)-3,4-dihydroxy-516 chlorobenzamide. 37. N-(1-adamantyl)-3,4-diacetoxy-5-cyanobenzamide. 38. N-(1-adamantyl)-3,4-dihydroxy-5-cyanobenzamide. 5 39. 3-(3-Ethoxycarbonylmethoxycarbamoyloxy-4-hydroxy-5-nitrophenyl)-1-phenylprop-2-en-1-one. 40. 3-(3,4-dihydroxy-5-nitrophenyl)-1-(2-carboxyphenyl)-prop-2-en-1-one. 10 41. 3-(3,4-dihydroxy-5-nitrophenyl)-1(4-nitrophenyl)-prop-2-en-1-one. 42. 2,5-bis-(3,4-dihydroxy-5-nitrobenzylidene)-cyclopentanone. 43. 1-Phenyl-3-(3-stearoyloxy-4-hydroxy-5-nitrophenyl)-prop-2-en-1-one. 44. 2-Cyano-3-(3,4-dihydroxy-5-nitrophenyl)-acrylic acid ethyl ester. 45. 3-(3,4-Dihydroxy-5-nitrobenzylidene)-4-ketopentanoic acid methyl ester. 46. 2-Cyano-3-(3,4-dihydroxy-5-nitrophenyl)-acrylamide. 47. B1,N-dimethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-acrylamide. 25 48. N,1H-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-acrylamide. 49. N-Isopropyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-acrylamide. 50. N'-Meiwi-N”-[2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-acryl]-piperazine. 51. 3,4-dihydroxy-5-nitrobenzyl-2-methoxyethyl ether. 52. 3,4-dihydroxy-5-nitrobenzylthio-acetic acid. 35 53. 2-(3,4-dihydroxy-5-nitrobenzyl)pyrrole. 54. Neopentyl ester of 3-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-acrylic acid. 40 55. N-(3-hydroxypropyl)-2-cyano-3(3,4-dihydroxy-5-nitrophenyl)-acrylamide. 56. 3-(4-hydroxy-5-nitro-3-pivaloyloxybenzylidene)-2,4-pentanedione. 57. 3,7-dihydroxy-5-nitrobenzyl-45 malonitrile. 58. 3,4-Dihydroxy-5-nitrobenzylcyanoacetic acid ethyl ester. 59. 2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)propanol. 50 60. A compound according to any one of claims 1 to 59, in the form of a simple salt or an acid addition salt. 61. A compound according to claim 60, wherein the salt is pharmaceutically acceptable. 62. A method for preparing compounds according to claim 1, characterized in that a compound of formula II: x in which R _p R ₂ and X have the meanings given in claim 1, is condensed in the presence of an acid or base catalyst with a compound of formula III: cn ₂ - R ₅ III which has an active methyl or methylene group and where R ₄ and R ₅ have the meanings defined in claim 1, thereby obtaining compounds of formula 1a: X 1a in which the double bond, if any, can be reduced to a single bond; or a ketone of formula IV: in which Rp Rj and X have the meanings defined in claim 1, and R ₆ represents hydrogen or alkyl, is condensed with an aldehyde of formula V: wherein R ₇ represents hydrogen, alkyl, alkoxy or dialkylamino group, to obtain a compound of formula lb: or a compound of formula VI: wherein R ₁ and R ₂ have the meanings defined in claim 1, is reacted with a cyclic acid anhydride of formula VII: wherein R, and R, are as defined in claim 1, to obtain a compound of formula 1e: -- ^With O. VII where m is 2-7, or with a dicarboxylic acid ester chloride of formula VIII: X 1e or a compound of formula II: Hal - (CO) - (CH,) - COR VIII π 2 m where ω is 2-7 and η is 0-1 and R is as defined in claim 1 and Hal is a halogen atom, to obtain a compound of formula IX: x where the aromatic ring is substituted with a group X to give a compound of formula 1c: (CO)„(CH,) _G - COR Ic which can be reduced to give a compound of formula Id: or an activated benzoic acid derivative of formula X: COY where R, Rj and X are as defined in claim 1 and Y represents halogen or some other activated group, reacts with an amine of formula XI: XI where R, and R1 have the meanings given in claim 1 and X is a halogen atom, is reacted with cuprocyanide in a polar, aprotic solvent at elevated temperature or optionally by treating 2,3-dihydroxybenzonitrile with hexamethylenetetramine to obtain a compound of formula II, where X is a cyano group. 63. A method according to claim 62, characterized in that the compounds of formula VI and VII are reacted in the presence of aluminum chloride. 64. A method according to claim 62, characterized in that the compound of formula 1c is reduced to a compound of formula Id by a Clemsen or WolffKishner reaction. 65. A method according to any one of claims 62 to 64, characterized in that it comprises an additional step of converting the product into its simple salt or acid addition salt. 66. A method for preparing compounds according to claim 1, described in any of Examples 1 to 63. 67. A pharmaceutical composition comprising as active ingredient a compound according to claim 1 and a pharmaceutically acceptable simple salt or acid addition salt thereof, mixed or associated with a pharmaceutically suitable carrier. 68. A composition according to claim 67, characterized in that it is in a form suitable for enteral administration. 69. A composition according to claim 68, characterized in that it is in the form of a tablet, capsule or drinking solution or suspension. 70. A composition according to claim 67, characterized in that it is in a form suitable for parenteral administration. 71. A composition according to claim 70, characterized in that it is in the form of an injectable solution. 72. A composition according to any one of claims 67 to 71, characterized in that it also contains levodopa. 10 73. A composition according to claim 72, characterized in that it also contains a peripheral decarboxylase inhibitor. 74. A composition according to claim 73, wherein the peripheral decarboxylase inhibitor is carbidopa. 75. A composition according to claim 73, wherein the peripheral decarboxylase inhibitor is benserazide. 76. Use of a compound according to any one of claims 1 to 61 for the manufacture of a medicament for the treatment of depression, Parkinson's disease, hypertension or heart failure.